Using thermal imaging for control of a manufacturing process

ABSTRACT

A thermal imaging camera monitors the temperature different zones in a pharmaceutical process such as ribbon compaction, coating, spray drying, fluid bed drying, high shear wet granulation, crystallization, lyophilization, precipitation, fermentation, and low dosage dispensing of a pharmaceutically active liquid. The thermal imaging camera can be used to produce a visual display of a temperature profile, or a spray pattern. In addition, feedback from the thermal imaging camera is used to control one or more processing parameters.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a division of U.S. nonprovisional application13/319,535, filed Nov. 9, 2011, which was a national stage entry ofInternational Application PCT/US10/34658, filed May 13, 2010, and claimsthe benefit of U.S. provisional application 61/178,540 filed 15 May 2009and of U.S. provisional application 61/233,593 filed 13 Aug. 2009.

FIELD OF THE INVENTION

This invention relates generally to the manufacture of chemical productssuch as pharmaceutical products, and particularly to the use of thermalimaging to monitor, and optionally, control, a variety of materialprocessing operations such as roller compaction, tablet coating, fluidbed drying, spray drying, lyophilization, crystallization,precipitation, fermentation, and preparation of low dosagepharmaceutical products using liquid dispensing technology.

BACKGROUND OF THE INVENTION

In the manufacture of pharmaceutical products, it is common to utilizean apparatus known as a “roller compactor” to compress a powdercomposition into a ribbon or into pellets for further processing orutilization. In a roller compactor, the powder composition is fed into anip between the peripheries of two opposed, counterrotating, rollers.

Feeding can be effected by any of a variety of feeding devices. Typicalfeeding devices include a screw feeder, which can have a single rotatingscrew, or a plurality of intermeshing screws, belt conveyors, which canhave one or more endless belts, and various other forms of conveyingdevices suitable for transporting a powder.

The peripheries of the rollers can be simple cylindrical surfaces, orthey can have mold cavities in which the powder is compacted and formedinto a desired shape. In the case of rollers having simple cylindricalsurfaces, the product of the roller compactor is typically in the formof a ribbon of compacted powder, which can be broken up, if desired, bya cutting device. On the other hand, if the rollers have mold cavitiesin their peripheries, they can deliver discrete pellets of compactedpowder.

Roller compaction has been successful for producing variouspharmaceutical products. However, product quality problems have beenencountered. It is possible to overcome these problems by makingadjusting various parameters of the operation of the compactor, butdoing so is difficult and requires a great deal of operator experience.In addition, some materials that are highly temperature sensitive, andmaterials that are processed at temperatures near their melting pointare particularly susceptible to problems when subjected to rollercompaction.

In tablet coating, which is typically carried out by spraying a coatingonto a bed of tablets being tumbled in a rotating drum-like device knownas a “coating pan” coating conditions such as the spraying rate, and therate of evaporation of the coating vehicle, affect tablet temperature.Accordingly measurement of tablet temperature is useful in monitoringthe coating operation and in controlling various coating parameters.Heretofore, temperature measurement in coating pans has been carried outusing various forms of thermometers such as non-contact infraredtemperature measurement devices and other forms of temperature probes.It has also recently been proposed to incorporate into a bed of tabletsone or more mobile temperature measurement devices, each having thesize, shape, and weight of one of the tablets being coated, andcontaining a temperature measuring device coupled to a miniaturetelemetry transmitter for sending temperature data to a remote receiveras a modulated radio signal.

The known temperature measurement devices used for monitoring coatingprocesses do not provide sufficient information for good control of thecoating operation, or for designing large coaters by “scaling up” on thebasis of temperature measurements taken using a smaller experimentalcoater. In particular, known temperature measurement devices used incoaters provide little information concerning the coater spray pattern,and are therefore of limited use in determining the relationship betweenthe rate of flow of coating material through the spray nozzles and theamount of coating deposited on the tablets.

In fluid bed drying, where warm air is caused to flow upward through abed of particulate material in a drying vessel, the temperature of thematerial tends to stratify, so that the temperatures in the lower partsof the dryer are higher than the temperatures in the upper parts. At thestart of a drying operation, the temperature differences betweendifferent levels are large. However, as drying proceeds, thetemperatures in the upper parts of the dryer increase, and thetemperature differences between the upper and lower parts tend todecrease. Thus, early in a drying operation, the temperature differenceis high. However, when new material is introduced into the fluid beddryer, whether in a continuous feed mode or in a batch mode, thetemperatures in the upper zones of material become higher. The result iseither that excessive drying occurs in the upper zones of the dryer, orthe time required for drying decreases. The latter is of course the moredesirable result.

The temperature differentials in a fluid bed dryer can be observed usingconventional thermal probes. However, conventional probes do not provideadequate information concerning the progressive changes in temperaturedifferentials that occur over time to enable an operator to controldrying parameters such as air temperature, material flow, and dryingtime.

In high shear wet granulation, a powder is subjected to the action of amoving blade in the presence of a binder applied to the material byspraying through one or more spray nozzles. The cooling that occurs dueto evaporation of the binder affects the granulation process, but doesnot take place uniformly within the granulator. Cooling is also affectedby the spray pattern of the nozzles. Conventional temperature probescannot adequately monitor the temperature variations in the material,which can occur both at the surface of the bed as a function of thespray pattern as in a coating operation, and within the bed, as in fluidbed drying.

In spray drying, a slurry of material is sprayed through a nozzle intoan atmosphere of heated air, which passes through an exhaust outlet.Conventional temperature measurement techniques used in spray dryingmeasure the temperature of the air at the exhaust outlet, and provideonly an indirect, and somewhat unreliable, indication of the actualtemperature of the sprayed material as it is being dried. Theseconventional techniques also lack the ability to monitor the spraycharacteristics and the temperature profiles within the spray pattern.

In lyophilization, quantities of a wet material are typically placed ina relatively large number of small vials, which are arranged on one ormore racks in a chamber in which temperature and pressure can becontrolled. The material is first frozen. Then, the pressure andtemperature in the chamber are adjusted to a level at which the water inthe frozen material sublimes. Thereafter, residual moisture is removedby applying a vacuum while maintaining the material at a controlledtemperature.

In a lyophilization chamber, the duration of each of the above steps istypically determined by measurement of the temperature in selectedvials. However, the materials in the vials tend to dry at differentrates depending on their location within the chamber, and also dependingon the materials themselves, which are not necessarily identical.Therefore, temperature measurement in selected representative vials doesnot always lead to optimal results.

In the preparation of low dosage pharmaceutical products using liquiddispensing technology, an array of pharmacologically inert carriertablets or similar substrates is transported past an array of dispensingnozzles that project very small, but accurately controlled doses of anactive pharmaceutical substance onto the carriers individually. Thedroplets are typically in the form of liquids containing the activesubstance either in solution or in suspension. The droplets formcoatings on the carriers, which adhere to the carriers. The carriers aretypically subjected to heating to evaporate the liquid component of thecoatings. Liquid dispensing technology or “LDT” is described in UnitedStates Patent Publication 2006/0017916, published Jan. 26, 2006, theentire disclosure of which is herein incorporated by reference.

In liquid dispensing technology, as in the other processes mentionedabove, the temperatures of different carriers in the array of carriersmoving past the dispensing nozzles can vary from one carrier to another,and if the heating of the carriers for evaporation of the liquidcomponent of the coatings is not properly controlled, some carriers andthe active material adhering thereto could be overheated or others couldbe insufficiently heated to evaporate the solvent or suspension medium.

Other manufacturing processes in which temperature measurement isutilized include crystallization, precipitation, fermentation and thelike, in all of which both spatial and temporal temperature variationsoccur, often in unpredictable patterns.

SUMMARY OF THE INVENTION

The manufacturing process in accordance with a first aspect of theinvention comprises three steps, which are not necessarily sequential.First a material, such as a pharmaceutical material, is subjected toprocessing in which the temperatures of plural different regions of thematerial are caused to differ from one another. These plural regions,which can be, but are not necessarily, all of the regions of thequantity of material, are scanned using a thermal imaging camera. In thescanning step, a set of data is generated, representing the temperaturesat multiple locations within each of the scanned regions. Processing canthen be controlled in response to the data generated in the scanningstep, and, in the controlling step, at least one processing parameter isadjusted in response to variations in the data. The processing stage canbe controlled in real time so that a quantity of material beingprocessed is directly affected by adjustment of processing parameters onthe basis of data acquired from that same quantity of material.Alternatively, for example in a batch process, temperature data derivedby scanning a first batch of material can be used to determine operatingparameters for subsequent process a second and different batch ofmaterial.

The invention is particularly advantageous when the manufacturingprocess is ribbon compaction, coating, spray drying, fluid bed drying,high shear wet granulation, crystallization, lyophilization,precipitation, fermentation, or low dosage dispensing of apharmaceutically active liquid.

The set of data can be displayed in the form of a two-dimensional image,e.g., a color image on a liquid crystal display screen where thepositions on the screen correspond to the locations within the regionsbeing scanned, and the colors represent the temperatures of the materialat those locations. In that case, the control of the at least oneprocess parameter can be carried out by a human operator, who caninterpret the displayed image and adjust one or more process parametersaccording to his or her interpretation of the displayed information.

Alternatively, the set of data generated in the scanning step can bedelivered as an electrical signal to an automatic controller, which cancontrol the processing step in response to the electrical signal. Theelectrical signal can be, for example, an amplitude-varying analogsignal, or one or more sequences of digital pulses, representingtemperature of various locations in the scanned regions as the regionsare scanned repeatedly by the thermal imaging camera.

In one embodiment of the invention, the process is roller compaction. Inroller compaction, physical properties, and in some cases chemicalproperties, of a compacted powder delivered by a roller compactor aredependent on certain operating parameters of the apparatus, includingthe rate at which the raw powder is fed to the nip, the rate of rotationof the rollers, the spacing of the rollers, and the temperature of therollers. These same parameters also affect the temperature of thecompacted material as it exits the nip of the compactor.

For example, if the rate at which the raw powder is fed to the nip isincreased, the pressure applied to the powder will increase, and, as aresult, the temperature of the compacted product will increase. If therate of rotation of the rollers decreases, the temperature of theproduct can increase for the same reason. On the other hand, if one orboth rollers are cooled sufficiently, for example by coolant flow,increasing the dwell time in the nip of the compactor by reducing therate of rotation of the rollers can result in a decrease in producttemperature. The spacing of the rollers can also affect the pressureapplied to the powder and thereby affect product temperature. And, ofcourse, coolant temperature can affect product temperature byconduction.

According to the invention, the temperature of the product is measuredimmediately as it exits the nip of the compactor. The measurement oftemperature of the product at the nip exit is made possible by the useof thermal imaging. By measuring the temperature of the compactedmaterial as it exits the nip, it is possible to regulate one or moreoperating parameters of the compactor, and thereby produce a uniformproduct having the desired properties. Thermal imaging to measureproduct temperature at the exit of the nip of the compactor can also beused as an analytical tool for process optimization and failure modeanalysis, especially since it enables the operator to observe theeffects of the adjustment of each of several operating parameters.

The compactor in accordance with the invention comprises a feederadapted to receive and transport a powder composition and a pair ofcounterrotating rollers having opposed peripheral surfaces. The rollersare disposed in relation to the feeder to receive the powder compositiontransported by the feeder between their opposed peripheral surfaces. Therollers apply pressure to the composition, and deliver, at a deliverylocation adjacent the rollers, a product consisting of a compressedversion of the composition. A thermal imaging camera, aimed at thedelivery location, detects the temperature of the product, and providesan output signal representing the temperature of the product. A controlconnected to the thermal imaging camera, and responsive to its outputsignal, regulates one or more operating parameters of the compactor. Theoperating parameters can be the rate at which the powder composition istransported by the feeder, the rate of rotation of the counterrotatingrollers, the spacing of the rollers, or the temperature of the rollers.

In the case in which the feed rate is controlled, the compactorpreferably includes a motor, responsive to the control, and arranged tooperate the feeder, and the control regulates the speed of the motor bydecreasing the speed of the motor with increasing product temperatureand increasing the speed of the motor with decreasing producttemperature.

In the case in which the rate of rotation of the rollers is controlled,the compactor preferably includes a motor, responsive to the control,and arranged to rotate the rollers, and the control regulates the speedof the motor. If the rollers are not chilled, the control preferablyincreases the speed of the motor with increasing product temperature anddecreases the speed of the motor with decreasing product temperature. Onthe other hand, if the rollers are sufficiently chilled, the control maybe set so that it decreases the speed of the motor with increasingproduct temperature and increases the speed of the motor with decreasingproduct temperature.

In the case in which the roller spacing is controlled, the compactorpreferably includes a spacing adjuster, responsive to the control, fordetermining the spacing of the rollers from each other, and the controlregulates the spacing of the rollers by increasing the spacing of withincreasing product temperature and decreasing the spacing withdecreasing product temperature.

In the case in which roller temperature is controlled, the compactorpreferably includes a temperature adjuster, responsive to the control,for determining the temperature of the rollers, and the controlregulates the temperature of the rollers by increasing the temperatureof the rollers with decreasing product temperature, and decreasing thetemperature of the rollers with increasing product temperature. Thecontrol can regulate any desired combination of operating parameters.

In coating, an infrared camera can be used to scan the surface of bed oftablets being tumbled in a coating pan and onto which a coating is beingsprayed by one or more nozzles. The temperature in the coating pan istypically controlled by controlling the temperature a supply of airdirected through the pan or by controlling the temperature of thecoating pan itself However, evaporation of solvent in the coatingmaterial causes cooling. Because of evaporative cooling, thermal imagingcan be used to monitor the spray pattern to detect nozzle clogging, andalso to determine empirically, based on the area of the bed being coatedas shown by the thermal image, and on previously accumulated data, therate at which coating material is being deposited onto the tablets, andcontrol of the spraying rate or other processing parameters can becarried out in response to the data derived from the thermal imagingcamera.

The ability of the thermal imaging camera to monitor spray patterns canalso be utilized to gain a better understanding of the manner in whichcoating material is deposited over time, and this information can beused in scaling up, i.e., in the design of larger coating apparatuses.

In fluid bed drying, thermal imaging can be utilized to monitor thetemperature profile of a dryer, thereby making it possible to carry outdrying more efficiently by reducing drying time as the temperatures inthe upper levels within the bed of material being dried progressivelyincrease over time.

In high shear wet granulation, a thermal imaging camera can be used tomonitor the temperature at the surface of the material being processedto monitor the pattern of sprayed binder by observing its evaporativecooling as in the coating process discussed above. In addition, athermal imaging camera can be used to monitor the temperature profile inthe granulation bowl and to detect excessive heating resulting from theuse of more shearing power than is necessary.

In the case of spray drying, thermal imaging makes it possible to obtaina direct measure of the temperature of the slurry of material as itexits the spray nozzle for improved control of processing parameterssuch as air supply rate, air supply temperature, and spraying pressure.The thermal imaging camera can be positioned outside the dryer as in thecase of a fluid bed dryer to monitor temperature profiles, or inside thedryer, where it can be used to monitor the temperature of the materialbeing sprayed and also to monitor the spray pattern.

In lyophilization, thermal imaging camera can observe the temperaturesof numerous lyophilization vials on a rack at the same time, and detectdifferences in temperature from one vial to another in order to controlvarious parameters such as vacuum, temperature and times for the severalstages in the lyophilization cycle so that optimum drying takes placewithout detriment to the product.

In preparation of pharmaceutical products using liquid dispensingtechnology, the temperatures of a large number of carriers in an arrayto which droplets are applied can be monitored, and temperaturedifferences can be detected so that process parameters can be controlledto avoid overheating and insufficient heating.

Various other applications of thermal imaging in material processing,and other details and advantages of the invention will be apparent fromthe following detailed description when read in conjunction with thedrawings.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic view showing a roller compactor equipped with athermal imaging camera and a control responsive to the thermal imagingcamera for regulating various operating parameters of the rollercompactor;

FIG. 2 is a schematic sectional view of a coating apparatus equippedwith a thermal imaging camera taken on a plane to which the axis ofrotation of the coating apparatus is perpendicular;

FIG. 3 is a schematic view of the tablet bed in the coating apparatus ofFIG. 2, showing a typical spray pattern;

FIG. 4 is a schematic side elevational view of a fluid bed dryerequipped with a thermal imaging camera arranged to obtain a temperatureprofile;

FIG. 5 is a schematic elevational view of a high shear granulatorequipped with two thermal imaging cameras, one arranged to scan thesurface of the material bed in the granulation bowls, and the otherarranged to obtain a temperature profile;

FIG. 6 is a schematic elevational view of a spray dryer equipped with athermal imaging camera arranged to scan the material being dried as itexits from the spray nozzle of the dryer;

FIG. 7 is a schematic elevational view of a lyophilization chamberequipped with a thermal imaging camera arranged to scan an array oflyophilization vials on a rack within the chamber;

FIG. 8 is a schematic elevational view showing a portion of a low liquiddispensing apparatus equipped with a thermal imaging camera; and

FIG. 9 is a schematic elevational view of a vessel for crystallizationprecipitation, fermentation or a similar process, equipped with athermal imaging camera.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

As shown in FIG. 1, a roller compactor 10 is provided with a hopper 12,for receiving material to be compacted. Material is fed from the hopper,by a feed screw 14 rotated by a motor 16, toward a pair of rollers 18and 20, which have their outer peripheral surfaces in opposedrelationship adjacent the lower end of the feed screw 14. The peripheralsurfaces of the rollers can be formed with recesses for molding thematerial fed by the screw 14 into pellets, and can have various othersurface configurations, depending on the desired result. The peripheralsurfaces of the rollers can also be simple cylinders.

Roller 18 is rotated by a motor 22, and coupled by gears or othersuitable drive means (not shown) to roller 20, so that both rollersrotate in opposite directions, but at the same peripheral speed.

An actuator 24, connected to roller 20, is provided to control therelative positions of the axes of rotation of the rollers, and therebyadjust the roller spacing.

In a roller compactor one or both of the rollers is typically providedwith internal passages for flow of a cooling liquid. In this case, thecooling liquid temperature is maintained at a desired level by means ofa chill temperature control 30.

A thermal imaging camera 26 is aimed at the exit of the nip betweenrollers 18 and 20, so that it can continuously monitor the temperatureof the product immediately as it is delivered by the compactor. By theuse of conventional gating techniques on the camera output signal, or byother electronic selection techniques, it is possible to select aportion of the image and to derive a temperature signal from only thatportion of the image. By selecting the portion of the image thatcorresponds to the product, and rejecting the portion of the image thatcorresponds to the rollers and any other surrounding components, thetemperature monitoring apparatus can discriminate between thetemperature of the product and the temperature of the rollers and othercomponents, and thereby obtain an accurate and continuous measurement ofproduct temperature. The selection is carried out in control apparatus28.

The control apparatus 28 also provides speed control signals to the feedscrew drive motor 16 and the roller drive motor 22, and providesadditional control signals to the roller spacing actuator 24 and thechill temperature control 30. These four control signals will ordinarilybe utilized individually. However, they can be used in any combination.When the signals are used in combination, their relative magnitudesshould be set so that each signal has the desired effect and so thatovershoot is avoided.

When the control apparatus 28 controls the speed of roller drive motor22, whether or not the motor speed is set to vary directly or inverselywith the monitored product temperature will depends on whether or notthe rollers are cooled and on the extent to which they are cooled. Ifthe chill temperature control 30 is operative, and a sufficient coolingeffect is sufficiently high, it will be desirable to set the control 28so that the speed of motor 22 varies inversely with product temperature.Thus, if the roller 18 is sufficiently cool, the roller speed candecrease with increasing product temperature. Doing so will increase theproduct dwell time in the roller nip and maintain a constant producttemperature. A similar inverse relationship between roller speed andproduct temperature can be utilized when the rollers are cooled withoutfeedback to the cooler form the thermal imaging camera.

The thermal imaging camera can also be used to monitor producttemperature without controlling any of the operating parametersfeedback. In this case, the effects of adjustment of operatingparameters such as feed rate, roller speed, roller spacing, and chilltemperature can be determined by varying each parameter individuallywhile holding the others at predetermined constant values. By monitoringthe effects of operating parameters in this manner, data on theperformance of a given compactor can be recorded and utilized in itsfuture operation for process optimization.

The apparatus depicted in FIG. 1 is only one example of variouscompactors in which the principles of invention can be utilized.

The particular feeder shown in FIG. 1, utilizes a single feed screw,tapered to produce some initial compaction of the powder before itreaches the rollers. The feeder can take various other forms which, forthe purposes of this invention, are equivalents of the screw feedershown. For example, the feeder can utilize a straight, non-tapered,screw, or a screw, either tapered or non-tapered, having a varyingpitch, preferably one in which the turns of the screw are progressivelycloser together as the conveyed material approaches the rollers. Otherequivalent feed devices such as belt conveyors incorporating a singleconveyor belt, two belts opposed to each other, or other beltarrangements, can be used. Any of numerous other conveyors suitable fortransporting powdered material can also be used and are equivalent tothe screw conveyor shown in FIG. 1.

The motors 18 and 22 are preferably electric motors such as DCservomotors, or the like. The motors may be equipped with suitable speedreduction gears or other transmissions if necessary. However, hydraulicmotors, and other forms of motors, such as turbines, etc. can be usedand, so long as their speeds can be controlled, they are consideredequivalents of the motors described.

The rollers 18 and 20 can be any suitable compacting rollers havingopposed peripheral surfaces. The peripheral surfaces can be cylindrical,or can have suitable recesses or other surface configurations. While therollers are preferably circular, rollers having various non-circularshapes, can be utilized so long as their peripheral surfaces cooperateto form a suitable compacting nip. Likewise, the rollers can be taperedin the same direction, in which case, their axes will not be parallel,or tapered in opposite directions. The rollers need not be the samesize, and more than two rollers can be used in some compactorconfigurations. Any such arrangement can be considered equivalent to therollers shown for the purpose of this invention.

The roller spacing actuator 24 can be any suitable actuator, such as anelectrically operated linear actuator having a rotary motor-and-rack andpinion gearing. However any of various other forms of actuator, such asa hydraulic actuator or the like can be utilized, and, for the purposeof this invention are equivalent to an electrically operated linearactuator.

The chill temperature control 30 is preferably a refrigeration devicehaving a heat exchange coil through which liquid is circulated to one orboth rollers through rotary seals or other suitable coupling devices. Inthe apparatus shown, the coolant is preferably circulated through theinterior of roller 18. However, coolant can be made to flow in contactwith the exterior of one or both rollers. Alternatively, air cooling,thermoelectric (Peltier effect) cooling, or other forms of cooling canbe utilized. All forms of controllable cooling devices suitable forcooling a compaction roller may be considered equivalent to the chilltemperature control 30 for the purpose of this invention.

The thermal imaging camera 26 can be any of various forms of thermalimaging camera that provide an output that is effectively an electronicrepresentation of the variations of temperature within the camera'sfield of view. Preferably the output of the camera is such thatinformation corresponding to a specific selected area in its field ofview can be selected and isolated.

The control 28 can be any of various forms of control devices, includingmicroprocessor-based controls, programmed logic array controls, discretelogic controls, and the like.

Various modifications other than those mentioned above can be made. Forexample, the thermal imaging camera can be aimed along a directionparallel to the axes of the rollers, in which case discriminationbetween the image of the product exiting the nip and the image of therollers and other components can be simplified. In addition, suitabletemperature shields can be utilized to improve image discrimination.

In FIG. 2, as a coating pan 32 rotates clockwise, a bed 34 of tabletswithin the pan is coated by spraying through a series of nozzles, one ofwhich is shown at 36 on a spray manifold 38. Nozzle 38 delivers acoating solution or suspension to the surface of the tablet bed as thebed is tumbled by rotation of the coating pan. The shape of the spraypatter 40 is determined by the nozzle structure, and is typicallygenerally conical. Plural nozzles disposed along the manifold deliverspray patterns 40, 42, etc., which can overlap, as shown in FIG. 3.

A thermal imaging camera 44, located inside the coating pan, and whichcan be mounted on the spray manifold 38, scans the surface of the tabletbed 34 as the coating is being sprayed. The electrical output of thecamera 44 is delivered to a control unit 46, which, in turn, controlsone or more coating parameters, which can include the temperature thesupply of air directed through the coating pan, the temperature of thecoating pan itself, the rate of rotation of the coating pan, spraypressure, spray temperature, and the duration of the coating cycle.Optionally, the output of the thermal imaging camera can be displayed ona screen such as an LCD video screen, so that the temperature of thesurface of the tablet bed can be monitored by a human operator.

Because of evaporative cooling of the solvent in the spray (or of thecarrier liquid in the case of a suspension), the thermal imaging camerais able to monitor the spray patters accurately. Thus not only is itpossible to detect nozzle failure due to clogging, but it is alsopossible to determine the rate at which coating material is beingdeposited onto the tablets, and to control of the spray pressure andother processing parameters in response to the data derived from thethermal imaging camera.

As mentioned previously, the ability of the thermal imaging camera tomonitor spray patterns can also be utilized to obtain a betterunderstanding the coating process for the purpose of designing largercoating pans on the basis of information obtained from laboratoryequipment.

FIG. 4 shows a fluid bed dryer 50, in which a bed 52 of particles isdried by heated air delivered upward through a perforated support 54from an air supply 56. The output of a thermal imaging camera 58disposed on a side of the dryer delivers an output to a control unit 60,which, in turn, can controls operating parameters of the air supply 57such as air flow rate and temperature. Alternatively, the thermalimaging camera can be used to control drying time, thereby achievingmore efficient operation by taking into account changes in thetemperature profile of the dryer that take place as successive batchesof material are processed and adjusting drying times accordingly. Theuse of thermal imaging to control processing parameters and/or dryingtimes is applicable to continuous fluid bed dryers as well as to batchmode dryers.

In the high shear wet granulation apparatus as shown in FIG. 5, a bed 62of material in a bowl 64 is mixed by a set of blades 66 operated by amotor 66, while being sprayed with a liquid binder through one or morespray nozzles 70. A first thermal imaging camera 72 is arranged abovethe bowl 64 so that it can monitor the temperature at the surface of thematerial bed 62 and thereby monitor the pattern of sprayed binder byobserving its evaporative cooling as in the coating process depicted inFIGS. 2 and 3. A second thermal imaging camera 74 is used to monitor thetemperature profile in the granulation bowl 64 and can be used to detectexcessive heating resulting from the use of excessive shearing power.Both thermal imaging cameras are connected to a control unit 76, which,in turn, can control various granulator operating parameters, such asbinder spray rate, motor speed and processing time.

In the spray drying system shown in FIG. 6, a spray nozzle 78 directs aslurry of material to be dried into an enclosure 80 having an air inlet82 and an air outlet 84. A thermal imaging camera 86 is arranged to scanthe spray pattern 88 adjacent the exit of the nozzle and thereby obtaina direct measure of the temperature of the slurry of material as itexits the spray nozzle. The output of the thermal imaging camera isconnected to a control unit 90, which can control various processingparameters such as air supply rate, air supply temperature, and spraypressure. As an alternative, the thermal imaging camera can bepositioned outside the dryer as in the case of a fluid bed dryer tomonitor temperature profiles.

In FIG. 7, an insulated lyophilization chamber contains a rack 94supporting a three-dimensional array of lyophilization vials 96. Thetemperature of the rack 94 and the level of vacuum in the chamber 92 arecontrolled by a control unit 98 in response to a signal derived from athermal imaging camera 100 inside the chamber and arranged to scan thetemperatures of the set of vials in the array. The thermal imagingcamera can detect differences in temperature from one vial to another,and can be used to control various parameters such as vacuum,temperature and times for the several stages in the lyophilization cycleso that optimum drying takes place without detriment to the product.

FIG. 8 shows a part of a liquid dispensing apparatus for producing lowdosage tablets by directing droplets of a pharmaceutically activematerial onto inert carrier tablets in accurately controlled volumes.The apparatus includes a conveyor which transports rows of carriertablets, one of which is shown endwise at 104, past a row 106 ofdispensing nozzles also shown endwise. The number of nozzles correspondsto the number of carrier tablets in each row. As a row of carriertablets passes the row of dispensing nozzles, each nozzle directs adroplet of active material onto the carrier. The rows of carrier tabletsare then transported underneath a heating apparatus 108. A thermalimaging camera 110 is arranged to scan all the tablets in a row and candetect temperature differences on the basis of which various processingparameters such as heating temperature, and the speed of the conveyormotor 112 can be controlled. In the embodiment shown, the camera islocated a short distance downstream from the heating apparatus.Alternatively, the camera can be located inside the heating apparatus.

In FIG. 9, reference number 114 designates a processing vessel which canbe one of a variety of vessels such as a crystallization vessel, afermentation vessel, a precipitation vessel or the like. The temperatureprofile of the vessel is monitored by a thermal imaging camera 116located to the side of the vessel. The thermal imaging camera deliversits output to a control unit 118, which is used to control one or moreprocessing parameters such as temperature and processing time.

In each of the embodiments described above, the thermal imaging cameracan be used to provide data from which processing parameters can becontrolled using conventional control techniques, both analog anddigital. Thermal imaging can be used to produce a visual display of atemperature profile, spray pattern or the like for human observation,and for human intervention in the control loop. Various modificationscan be made to the apparatus and processes described. It is possible toutilize multiple thermal imaging cameras to observe separately differentregions of a material undergoing processing, as in the case of alyophilization chamber having multiple racks at different levels, forexample. Feedback from the thermal imaging camera can be utilized forreal time control of processing parameters, and thermal imaging dataderived form a processing operation on a quantity of material can alsobe used for determination of parameters for subsequent processingoperations on other quantities of the same material.

Still other modifications may be made to the apparatus and methodsdescribed above without departing from the scope of the invention asdefined in the following claims.

What is claimed is:
 1. A process for coating tablets comprising sprayinga coating material in a liquid by at least one spray nozzle onto saidtablets while said tablets are in a rotating coating pan, said liquidbeing a solvent in which the coating material is dissolved, or a carrierin which the coating material is suspended, in which said liquid iscaused to evaporate while in contact with said tablets whereby thecoating material is deposited onto said tablets, and in which thetemperatures of plural regions of said tablets in the rotating coatingpan differ from one another through evaporative cooling as said liquidevaporates, the process further comprising scanning said regions using athermal imaging camera, thereby generating a set of data representingtemperatures in said plural regions, and adjusting at least oneprocessing parameter in response to said data, said at least oneprocessing parameter being a parameter from the group consisting of thepressure applied to said liquid upstream of said at least one spraynozzle, the rate of rotation of said coating pan, the temperature ofsaid coating pan, the temperature of coating material being sprayed bysaid at least one spray nozzle, the temperature of a supply of airdirected through said coating pan, and the duration of said process. 2.The process according to claim 1, in which the coating material issprayed by applying pressure to said liquid upstream of said at leastone spray nozzle, said set of data is delivered as an electrical signalto an automatic controller, and said controller controls said pressure.3. The process according to claim 1, in which said set of data isdelivered as an electrical signal to an automatic controller, and saidcontroller controls the rate of rotation of the coating pan.
 4. Theprocess according to claim 1, in which said set of data is delivered asan electrical signal to an automatic controller, and said controllercontrols the temperature of the coating pan.
 5. The process according toclaim 1, in which said set of data is delivered as an electrical signalto an automatic controller, and said controller controls the temperatureof the liquid sprayed though said at least one spray nozzle.
 6. Theprocess according to claim 1, in which a supply of air is directedthrough the coating pan, in which said set of data is delivered as anelectrical signal to an automatic controller, and said controllercontrols the temperature of said air supply.
 7. The process according toclaim 1, in which said set of data is delivered as an electrical signalto an automatic controller, and said controller controls the duration ofsaid process.
 8. The process according to claim 1, in which said coatingmaterial in a liquid is sprayed by an array of spray nozzles onto saidtablets, and in which said data is utilized to detect failure of one ormore of said spray nozzles.
 9. A process of lyophilization comprisingsubjecting plural vials, each containing a substance to be dried, to acontrolled vacuum and temperature in a lyophilization chamber, scanningsaid vials using a thermal imaging camera, thereby generating a set ofdata representing temperatures in said vials, and adjusting at least oneprocessing parameter in response to said data, said at least oneprocessing parameter being a parameter from the group consisting of thevacuum level in said lyophilization chamber, the temperature in saidlyophilization chamber, and the duration of at least one stage of thelyophilization process.